Protease-activated receptor-1 deficiency protects against streptozotocin-induced diabetic nephropathy in mice.
Protease-activated receptor-1 deficiency protects against streptozotocin-induced diabetic nephropathy in mice.
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DOI：
10.1038/srep33030
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发表时间：
2016-09-13
影响因子：
4.6
通讯作者：
Spek CA
中科院分区：
文献类型：
--
作者：
Waasdorp M;Duitman J;Florquin S;Spek CA
内源性活化蛋白 C 以蛋白酶激活受体 1 (PAR-1) 依赖性方式改善糖尿病肾病 (DN)，表明 PAR-1 激活限制了 DN 的进展。然而，成纤维细胞样细胞中 PAR-1 的激活会诱导增殖和细胞外基质产生，从而导致纤维化疾病。考虑到 DN 期间系膜增殖和细胞外基质生成的关键作用，PAR-1 实际上可能会增强糖尿病引起的肾损伤。为了确定 PAR-1 对 DN 的净效应，在野生型和 PAR-1 缺陷小鼠中研究了链脲佐菌素诱导的 DN。通过在体外评估 PAR-1 刺激和抑制后系膜和肾小管上皮细胞的促纤维化反应，获得了后续的机制见解。尽管血糖水平相似，但 PAR-1 缺陷小鼠在诱发糖尿病后出现的肾损伤较少，表现为蛋白尿、血浆胱抑素 C 水平降低、系膜区域扩张和肾小管萎缩。在体外，系膜细胞中的 PAR-1 信号传导导致基质蛋白纤连蛋白和 IV 型胶原的增殖和表达增加。相反，在糖尿病 PAR-1 缺陷小鼠中观察到增殖和纤连蛋白沉积均减少。总的来说，我们表明 PAR-1 在 DN 的发展中发挥着重要作用，因此 PAR-1 可能是 DN 中有吸引力的治疗靶点。
Endogenously administered activated protein C ameliorates diabetic nephropathy (DN) in a protease-activated receptor-1 (PAR-1)-dependent manner, suggesting that PAR-1 activation limits the progression of DN. Activation of PAR-1 in fibroblast-like cells, however, induces proliferation and extracellular matrix production, thereby driving fibrotic disease. Considering the key role of mesangial proliferation and extracellular matrix production during DN, PAR-1 may in fact potentiate diabetes-induced kidney injury. To determine the net effect of PAR-1 in DN, streptozotocin-induced DN was studied in wild type and PAR-1 deficient mice. Subsequent mechanistic insight was obtained by assessing profibrotic responses of mesangial and tubular epithelial cells in vitro, following PAR-1 stimulation and inhibition. Despite having similar glucose levels, PAR-1 deficient mice developed less kidney damage after induction of diabetes, as evidenced by diminished proteinuria, plasma cystatin C levels, expansion of the mesangial area, and tubular atrophy. In vitro, PAR-1 signaling in mesangial cells led to increased proliferation and expression of matrix proteins fibronectin and collagen IV. Conversely, a reduction in both proliferation and fibronectin deposition was observed in diabetic PAR-1 deficient mice. Overall, we show that PAR-1 plays an important role in the development of DN and PAR-1 might therefore be an attractive therapeutic target to pursue in DN.
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影响因子：
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